JP2003192573A - Oral gel preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an easily-administrable and easily-swallowable oral gel preparation easily swallowable in the oral administration of a slightly water-soluble medicine to a baby, an elderly person, a patient having swallowing difficulty, a shut-in patent after operation or the like, allowing a prescribed amount in which sufficient medicinal effects can be achieved to be precisely administered, and improved so that the labor of a caregiver can be reduced when administering the preparation to a patient requiring the care. <P>SOLUTION: This oral gel preparation is obtained by dispersing a medicament slightly soluble in water in a gel. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an oral gel preparation in which a poorly water-soluble drug is dispersed in a gel.

[0002]

2. Description of the Related Art Currently, poorly water-soluble drugs are mainly formulated as oral preparations in the form of solid preparations such as tablets, pills, granules, capsules and powders. However, for infants, the elderly, and patients with dysphagia, these drugs have the disadvantage that they are difficult to take (swallow), and it is difficult to say that these dosage forms are easy to take. That is, when the drug is administered in the form of a solid formulation such as a tablet due to functional deterioration associated with aging and food intake dysfunction (eg dysphagia) due to senile dementia, etc. In some cases, it may get stuck or cannot be swallowed because it remains in the oral cavity, resulting in insufficient drug effect. In addition, depending on the size of the tablets or pills, they may become clogged in the throat, making it difficult to take them. Aspiration of a drug or the like (incorrect intake of food into the trachea) causes great pain for the patient and may cause pneumonia.

When administered as a liquid or syrup, it is much easier to swallow than a solid preparation such as tablets, but it is difficult to use a water-insoluble drug as a syrup. Moreover, the risk of aspiration of the syrup is extremely high.

In particular, elderly people and patients with cerebral infarction often have dysphagia, and in postoperative bedridden patients,
There is a big problem that it is difficult to take solid agents or liquid agents such as tablets, pills, granules, powders and capsules, syrups, etc. in such a bedridden state.

Further, in terms of packaging form, the drug can be easily taken out from the container, and can be taken directly from the container.
There is a demand for reliable administration without aspiration and good disposability.

Further, it is a problem that a caregiver who cares for an elderly person and a bedridden patient is required to take a considerable amount of time when taking a drug, which is a problem.

Cilostazol is a drug which has been widely used in the form of tablets as an antiplatelet drug. In addition, it also has a cerebral circulation improving action, and is regarded as promising as a preventive and therapeutic agent for cerebral infarction. Since cilostazol is poorly soluble in water, all cilostazol preparations currently on the market are tablets.

[0008]

Under the present circumstances where the above problems are posed, oral administration of a poorly water-soluble drug to infants, the elderly, patients with dysphagia, postoperative bedridden patients, etc. It can be swallowed easily, and it can reliably take a certain amount that can obtain a sufficient drug effect, and it also reduces the time and effort of the caregiver when taking the drug in patients who need care. An object is to provide an improved swallowable oral gel preparation that is easy to take.

[0009]

Means for Solving the Problems The inventors of the present invention have made extensive studies to achieve the above object, and have investigated various more effective dosage forms for oral administration of a poorly water-soluble drug. As a result, when a poorly water-soluble drug was dispersed in the gel, an oral gel preparation that was extremely easy to take for infants, the elderly, and patients with dysphagia could be obtained. In addition,
A poorly water-soluble drug has poor miscibility with a gelling agent, does not disperse uniformly during gelation, and easily traps air bubbles and is difficult to remove. For this reason, the dispersant is used to disperse the drug, but it is not preferable to use a large amount of the additive from the viewpoint of safety and economy. However, by using the low-methoxylated pectin as the gelling agent, the dispersion of the drug in the gel was uniformly maintained for a long period of time without using a dispersant, and an oral gel preparation with good stability could be obtained. .

Further, the inventors of the present invention have conducted further studies, and since the container used for the preparation has a gel-like property, it is easy to take the drug. In order to reduce the caregiver's time and avoid contact with drugs, and in consideration of disposability, preferably a suitable disposable container, for example, a bag type, a straw type,
It is supposed to be a disposable container such as ampoule type and syringe type.

That is, the present invention provides (1) an oral gel preparation characterized in that a poorly water-soluble drug is dispersed in the gel, and (2) the gel is a low methoxylated pectin gel. (3) The oral gel preparation according to the above (1) or (2), wherein the poorly water-soluble drug is cilostazol or a pharmaceutically acceptable salt thereof. The oral gel preparation according to (3) above, wherein cilostazol or a pharmaceutically acceptable salt thereof is contained at a concentration of 0.01 to 20% (W / V).
(5) Oral according to any one of (2) to (4) above, wherein another high molecular polysaccharide derived from a natural product is blended in a proportion of 50% or less by mass ratio to the low-methoxylated pectin. Gel preparation, (6) Oral gel preparation according to (5) above, wherein the other high molecular polysaccharide derived from natural products is agar and / or carrageenan, (7) Single dose is enclosed in a disposable container The present invention also relates to the oral gel preparation according to any one of (1) to (6) above.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION A drug which is poorly soluble in water is defined by the Japanese Pharmacopoeia as “insoluble” (solubility = 0.1 to 1.0%) and “extremely insoluble” (solubility = 0.01 to 0). 0.1%) or "almost insoluble" (solubility = 0.01% or less). Drugs that are poorly soluble in water include, for example, cilostazol (antiplatelet agent), norfloxacin (antibacterial agent), alacepril (antihypertensive agent), probucol (hyperlipidemic agent), teprenone (peptic ulcer agent),
Domperidone (antiemetic), theophylline (bronchodilator) and the like. Among them, cilostazol is regarded as a promising drug for the prevention and treatment of cerebral infarction, so that it is extremely significant to make an oral gel preparation especially for patients with cerebral infarction who often have dysphagia.

The gel is preferably a naturally occurring polymer polysaccharide or protein such as low methoxylated pectin, high methoxylated pectin, agar, carrageenan, guar gum, gellan gum, xanthan gum, locust bean gum, gelatin, etc. The gelling agent usually used in 1. can be used after swelling with water.
In particular, low-methoxylated pectin and locust bean gum are preferable because the drug can be uniformly dispersed over a long period of time. Of these, low-methoxylated pectin is
It is particularly preferable because it has established safety as a pharmaceutical additive.

A low-methoxylated pectin gel can be obtained by gelling an aqueous solution of low-methoxylated pectin, usually with a divalent metal ion such as calcium.
The amount of the low methoxylated pectin used can be appropriately changed depending on the drug used and the like, but is usually about 0.3-
The concentration is preferably 5% (W / V). Here, the low-methoxylated pectin is obtained by further demethylating pectin extracted from a fruit skin or the like, so that the proportion of methyl ester in galacturonic acid, which is one of the constituent sugars, is about 50%.
It is as follows. Generally, pectin has been widely added to foods as a thickener since ancient times, and JECFA (F
Since it is regarded as a harmless food additive based on the result of the toxicity test by AO / WHO, Joint Committee on Food Additives), it is an extremely safe food material with no usage restrictions. In addition, various grades of low-methoxylated pectin are commercially available for use as additives for pharmaceuticals and foods, and suitable commercial products can be appropriately selected and used in the present invention.

A water-soluble calcium salt is particularly preferable as a source of the divalent metal ion used for gelling the low-methoxylated pectin. Examples thereof include edible calcium compounds such as calcium lactate, calcium chloride, calcium gluconate, and calcium acetate, which are edible and have no problem. The amount of these used can be an optimum amount capable of gelating the low methoxylated pectin. Since the technology relating to gelation has been well established in the past, such known technology can be adopted in the present invention.

To the oral gel preparation of the present invention, for the purpose of improving the swallowability, a high molecular polysaccharide derived from a natural product other than the low methoxylated pectin among the above gelling agents is added. You can For example, various gelling agents generally used in the field of foods, for example, highly methoxylated pectin, agar, carrageenan, guar gum, gellan gum, xanthan gum, locust bean gum and the like can be used alone or in combination of two or more. In particular, it is preferable to use agar and / or carrageenan (κ type, ι type, λ type), which are high molecular polysaccharides derived from seaweed, from the viewpoint of safety and swallowability. The use ratio of these can be adjusted appropriately, but in order not to hinder the homogenization of the drug, the weight ratio (dry) to the low-methoxylated pectin is about 50% or less, preferably about 40% or less. Is good.

In the oral gel preparation according to the present invention, in addition to the drug, the gelling agent and the divalent metal ion, various additives which are acceptable as additives for oral pharmaceuticals can be appropriately added as necessary. Examples of the additives include stabilizers, water retention agents, pH adjusters, sweeteners, dispersants, preservatives and fragrances. Examples of the stabilizer include ascorbic acid, tocopherol, edetate and the like. Examples of the water retention agent include glucose, fructose, xylitol and the like. Examples of the pH adjusting agent include citric acid, malic acid, succinic acid, acetic acid and salts thereof. Examples of the sweetener include sucrose, sorbitol, trehalose and the like. Examples of the dispersant include carboxymethyl cellulose, sodium alginate, hydroxypropyl cellulose and the like. As the preservative, for example,
Paraoxybenzoic acid ester, potassium sorbate, etc. are mentioned. Examples of the fragrance include menthol, fruit juice, and other essential oils.

Cilostazol is represented by the formula 6-
It is [4- (1-cyclohexyl-1,2,3,4-tetrazol-5-yl) butoxy] -3,4-dihydrocarbostyril.

[Chemical 1]

The pharmaceutically acceptable salt of cilostazol can be easily formed by reacting the above ciloxazole with a pharmaceutically acceptable acid.
Examples of the pharmaceutically acceptable acid include hydrochloric acid,
Examples thereof include inorganic acids such as sulfuric acid, phosphoric acid and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, malic acid, tartaric acid, citric acid and benzoic acid.

When cilostazol is formulated in the present invention, the content of cilostazol or a pharmacologically acceptable salt thereof can be appropriately determined by the usage method and the like. Preferably, the concentration of the active ingredient is about 0.0 in the oral gel preparation.
1 to 20% (W / V). The solubility of cilostazol is about 0.0003%.

The oral gel preparation according to the present invention can be produced according to a usual method for producing an oral gel preparation. For example, first, a gelling agent, a bulk drug and various additives are added to purified water, and the mixture is stirred and heated to form a uniform suspension. The order of mixing the components is not particularly limited, and all the components may be mixed at the same time, or only some of the components may be dissolved in purified water first, and then the remaining components may be dissolved. . Further, if desired, additives (calcium salt, etc.) can be added. After filling a container such as a bag, a straw, an ampoule, or a syringe for each dose, and cooling to room temperature, a gelled, one-time-use container preparation can be obtained. The drug, which is the main ingredient of the gelled oral gel preparation of the present invention, is in a uniformly dispersed state. If the dispersion of the drug in the gel is kept uniform for a long period of time, there will be a concentration difference in the manufacturing tank and the drug content of the product will vary, and the drug will settle in the container and remain in large quantities. It has the advantage that it does not get lost.

If desired, the syringe type may be solidified by cooling and then gelated, and then freeze-dried in order to impart more stability. When the lyophilized product is taken, it absorbs a certain amount of water from the mouth of the syringe to moisturize the inside to cause gelation, thereby forming a form that is easy to take.

As the container, various types of containers can be appropriately adopted depending on the purpose. In particular, a disposable container is preferable, and a safe plastic container is preferable. Examples of the container include a bag type, a straw type, an ampoule type, and a syringe type. [Fig. 1]
~ [Fig. 4] shows a bag-type, straw-type, ampoule-type, and syringe-type container for an oral gel preparation. The bag type of [Fig. 1] is opened from the cut, the opening is put in the mouth, and the contents are squeezed out and taken. The straw type of FIG. 2 is taken by folding or cutting both ends, or removing the sealing material at both ends, and holding one end in the mouth and sucking. In the ampoule type shown in FIG. 3, the tip is opened and held in the mouth, and then the air chamber at the rear end is pressed to take out the content and take it. The syringe type of [Fig. 4] removes the sealing material at the tip, holds it in the mouth, and pushes the piston to take out the content and take it. These containers are crushed to an appropriate size by the action of extruding, they are pleasant to suffocate, and they can reliably take a single dose, which makes them extremely useful in terms of operability, safety of administration, and certainty. . The straw type, ampoule type, and syringe type of [FIG. 2] to [FIG. 4] are particularly preferable in that almost no leftover beverage remains in the container. On the other hand, the bag type of FIG. 1 is easy to manufacture and low in cost.

[0024]

EXAMPLES Examples of the present invention will be described below, but the following disclosure is merely specific examples of the present invention and does not limit the technical scope of the present invention.

Example 1 [Formulation Example] The following components were added to purified water so that the total amount was 10 liters, and the mixture was heated to 80 ° C. and uniformly mixed. next,
Add 5 g of calcium lactate and mix evenly until 10
Each polyethylene bag (mL side = approx. 7 cm)
After filling and sealing, the mixture was cooled to room temperature to obtain an oral gel preparation. Cilostazol 100 g Low-methoxylated pectin (manufactured by San-Ei Gen FFI Co., Ltd.) 152 g Agar (manufactured by San-Ei Gen FFI Co., Ltd.) 48 g Glucose 500 g Potassium sorbate 8 g Orange Essence 24 g

Example 2 [Formulation Example] The following components were added to purified water so that the total amount was 10 liters, and the mixture was heated to 80 ° C. and uniformly mixed. next,
Add 5 g of calcium lactate and mix evenly until 10
Each polyethylene bag (mL side = approx. 7 cm)
After filling and sealing, the mixture was cooled to room temperature to obtain an oral gel preparation. Cilostazol 100 g Low-methoxylated pectin (manufactured by San-Ei Gen FFI Co., Ltd.) 152 g κ-carrageenan (manufactured by San-Ei Gen FFI Co., Ltd.) 48 g Xylitol 500 g Potassium sorbate 8 g Orange essence 24 g

Test Example 1 The preparations obtained in the above Examples were stored at 25 ° C. with the long sides standing vertically, and the appearance was visually observed. Further, the contents of the drug were measured by HPLC by sampling from the upper part, the middle part and the lower part.

The results are shown in the table below.

[Table 1] As is clear from the results in Table 1, the stability of the oral gel preparation of the present invention was good.

Test Example 2 In the above example, at the start of filling, 30 minutes after the start of filling,
The drug content of each product after 1 hour and at the end of filling was measured by HPLC.

The results are shown in the table below.

[Table 2] As is clear from the results in Table 2, the oral gel preparation of the present invention showed almost no variation in the content of each product.

[0031]

EFFECT OF THE INVENTION The oral gel preparation according to the present invention can be used for infants and the elderly by providing a poorly water-soluble drug in a gel form and by adopting a container according to the purpose.
Or, it can be taken easily by patients with dysphagia, and should be sure to take a certain amount to obtain a sufficient drug effect without causing pain to the patient or risk of aspiration. Further, it has been improved so that the caregiver's time and effort can be reduced when taking a drug in a patient requiring care.

Further, since the uniform dispersibility of the drug is maintained for a long period of time, the drug content may vary in the product,
A large amount of drug does not remain in the drug container after taking. Furthermore, the oral gel preparation of the present invention is extremely safe since it can produce a high quality product without adding a large amount of a surfactant as a dispersant.

[Brief description of drawings]

FIG. 1 shows a bag-type container for an oral gel preparation.

FIG. 2 is a view showing a straw type container for an oral gel preparation.

FIG. 3 shows an ampoule-type container for an oral gel formulation.

FIG. 4 shows a syringe-type container for an oral gel formulation.

[Explanation of symbols]

1 Oral gel formulation Two bag container break 3 Sealant 4 ampoule air chamber 5 syringe piston

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Keiichi Kawakami             21-21 Nishinosu, Taihama, Kitajima-cho, Itano-gun, Tokushima Prefecture (72) Inventor Fujio Inoue             41, 240 Odai, Otsu Town, Naruto City, Tokushima Prefecture F term (reference) 4C076 AA09 BB01 CC14 EE30A                       FF02 FF68                 4C086 AA01 AA02 BC62 GA07 MA02                       MA03 MA05 MA27 MA52 ZA54

Claims (7)

[Claims] 1. An oral gel preparation characterized in that a poorly water-soluble drug is dispersed in the gel. 2. The oral gel preparation according to claim 1, wherein the gel is a low methoxylated pectin gel. 3. The oral gel preparation according to claim 1 or 2, wherein the poorly water-soluble drug is cilostazol or a pharmacologically acceptable salt thereof. 4. The oral gel preparation according to claim 3, wherein cilostazol or a pharmacologically acceptable salt thereof is contained at a concentration of 0.01 to 20% (W / V). 5. The oral gel according to any one of claims 2 to 4, wherein another high molecular polysaccharide derived from a natural product is blended in a proportion of 50% or less by mass ratio with respect to the low methoxylated pectin. Formulation. 6. The oral gel preparation according to claim 5, wherein the high molecular polysaccharide derived from other natural products is agar and / or carrageenan. 7. The oral gel preparation according to claim 1, wherein a single dose is enclosed in a disposable container.